ACUTE TOLERANCE TO SPINALLY ADMINISTERED MORPHINE COMPARES MECHANISTICALLY WITH CHRONICALLY INDUCED MORPHINE-TOLERANCE

The mechanistic similarity between acutely and chronically induced mor phine tolerance has been previously proposed but remains largely unexp lored. Our experiments examined the modulation of acutely induced tole rance to spinally administered morphine by agonists that affect the N- methyl-D-aspartate receptor and nitric oxide synthase systems. Antinoc iception was detected via the hot water (52.5 degrees C) tail flick te st in mice. Intrathecal pretreatment with morphine (40 nmol) produced a 9.6-fold rightward shift in the morphine dose-response curve, This s hift confirmed the induction of acute spinal morphine tolerance, Intra thecal copretreatment with the receptor antagonists (competitive and n oncompetitive, respectively) dizolcipine (MK801, 3 nmol) or LY235959 ( 4 pmol) and morphine [40 nmol, intrathecally (i.t.)] attenuated acute tolerance to morphine measured 8 hr later. A 60-min pretreatment of 7- nitroindazole (6 nmol, i.t.), a selective neuronal NOS inhibitor, foll owed by administration of morphine (40 nmol, i.t.) blocked the inducti on of morphine tolerance. Intrathecal copretreatment with morphine (40 nmol, i.t.) and agmatine (4 nmol, i.t.), an imidazoline, receptor ago nist and putative nitric oxide synthase inhibitor, almost completely a bolished acute spinal morphine tolerance. The results of these experim ents agree with previous reports using models of chronically induced m orphine tolerance. This evidence supports the proposal that the mechan isms responsible for acute morphine tolerance parallel those underlyin g chronic morphine tolerance. This study attests to the powerful predi ctive value of acute induction as a model for morphine tolerance.